the administration of deferasirox in an iron-overloaded dialysis patient

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Letter to the Editor The administration of deferasirox in an iron-overloaded dialysis patient To the Editor: Iron overload has been implicated as a nontraditional risk factor for cardiovascular diseases in patients with chronic kidney disease (CKD) and end stage renal disease (ESRD). 1,2 Given this fact, iron overload not only offers clinical prognostic value, but will be an emerging therapeutic target in CKD and dialysis patients. Here, we present a case involving a dialysis patient with severe hemochromatosis who underwent successful treatment. Since January 2008, a 59-year-old male patient had been suffering from an intractable malaise. He had a history of paroxysmal nocturnal hemoglobinuria (PNH) and received maintenance dialysis therapy for ESRD since September 2007. The PNH was initially diagnosed in 1984 and gradually became transfusion dependent. In the 1990s, the frequency of transfusion was seasonal, and then became monthly in the 2000s. The first biochemical examination in our hospital revealed serum iron levels to be 181 mg/dL (normal 30–180 mg/dL), total iron-binding capacity to be 192 mg/dL (normal 250–450 mg/dL), trans- ferrin saturation to be 94.3%, and ferritin levels to be 7420 ng/mL (normal 21.8–274.66 ng/mL). After develop- ing into ESRD, the patient required frequent transfusions with packed red blood cells (PRBC; 500 mL biweekly) in addition to the aggressive use of an erythropoiesis- stimulating agent for refractory anemia to maintain hemo- globin levels at approximately 8.0–9.0 g/dL. Given the history of refractory anemia and regular component therapy accompanied by severe intractable malaise and a soaring serum ferritin level, a clinical diagnosis of chronic iron overload was made. Chelating therapy with deferox- amine (DFO, Desferal; Novartis Pharmaceuticals, Basel, Switzerland) was initiated in May 2008. One year later, the patient’s serum ferritin concentration exceeded 12,000 ng/mL, and was accompanied by severe exertional dyspnea and chronic hepatitis. Abdominal magnetic reso- nance imaging (MRI) revealed a decreasing signal in both the liver and the spleen (Figure 1). Given the poor response to DFO, an alternative chelating agent, defera- sirox (Exjade; Novartis Pharmaceuticals), was considered despite it not being approved for the ESRD population in either Taiwan or by the US Food and Drug Administration (FDA). After obtaining the patient’s consent, 750 mg (15 mg/kg/d) of deferasirox was administered daily since July 2009. The patient’s serum ferritin levels declined steadily to 3252 ng/mL under the maintenance dosage of 500 mg/d (10 mg/kg/d) that was initiated in December 2010 (Figure 2). In this PNH patient with ESRD, renal anemia further aggravated the transfusion demand for this rare disorder that is characterized by defective hematopoiesis. 3 Iron overload was therefore inevitable in our patient given the multiple and frequent blood transfusions, approximating at least 300 units of PRBC (unit of blood = 250 mL) so Correspondence to: Y.-M. Chen, MD, Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin 640, Taiwan. E-mail: [email protected] Potential conflicts of interest. All authors: no conflicts. Funding: No funding sources. Figure 1 Secondary hemochromatosis. Axial magnetic reso- nance imaging with the T2-weighted fast-recovery fast spin-echo (FRFSE) sequence demonstrated significant accen- tuated decreases in liver and spleen signal intensities. Hemodialysis International 2012; ••:••–•• © 2012 The Authors Hemodialysis International © 2012 International Society for Hemodialysis DOI:10.1111/j.1542-4758.2012.00704.x 1

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Page 1: The administration of deferasirox in an iron-overloaded dialysis patient

Letter to the Editor

The administration of deferasirox in aniron-overloaded dialysis patient

To the Editor:Iron overload has been implicated as a nontraditionalrisk factor for cardiovascular diseases in patients withchronic kidney disease (CKD) and end stage renaldisease (ESRD).1,2 Given this fact, iron overload not onlyoffers clinical prognostic value, but will be an emergingtherapeutic target in CKD and dialysis patients. Here, wepresent a case involving a dialysis patient with severehemochromatosis who underwent successful treatment.

Since January 2008, a 59-year-old male patient hadbeen suffering from an intractable malaise. He had ahistory of paroxysmal nocturnal hemoglobinuria (PNH)and received maintenance dialysis therapy for ESRD sinceSeptember 2007. The PNH was initially diagnosed in1984 and gradually became transfusion dependent. In the1990s, the frequency of transfusion was seasonal, andthen became monthly in the 2000s. The first biochemicalexamination in our hospital revealed serum iron levels tobe 181 mg/dL (normal 30–180 mg/dL), total iron-bindingcapacity to be 192 mg/dL (normal 250–450 mg/dL), trans-ferrin saturation to be 94.3%, and ferritin levels to be7420 ng/mL (normal 21.8–274.66 ng/mL). After develop-ing into ESRD, the patient required frequent transfusionswith packed red blood cells (PRBC; 500 mL biweekly) inaddition to the aggressive use of an erythropoiesis-stimulating agent for refractory anemia to maintain hemo-globin levels at approximately 8.0–9.0 g/dL. Given thehistory of refractory anemia and regular componenttherapy accompanied by severe intractable malaise and asoaring serum ferritin level, a clinical diagnosis of chroniciron overload was made. Chelating therapy with deferox-amine (DFO, Desferal; Novartis Pharmaceuticals, Basel,Switzerland) was initiated in May 2008. One year later,

the patient’s serum ferritin concentration exceeded12,000 ng/mL, and was accompanied by severe exertionaldyspnea and chronic hepatitis. Abdominal magnetic reso-nance imaging (MRI) revealed a decreasing signal in boththe liver and the spleen (Figure 1). Given the poorresponse to DFO, an alternative chelating agent, defera-sirox (Exjade; Novartis Pharmaceuticals), was considereddespite it not being approved for the ESRD population ineither Taiwan or by the US Food and Drug Administration(FDA). After obtaining the patient’s consent, 750 mg(15 mg/kg/d) of deferasirox was administered daily sinceJuly 2009. The patient’s serum ferritin levels declinedsteadily to 3252 ng/mL under the maintenance dosage of500 mg/d (10 mg/kg/d) that was initiated in December2010 (Figure 2).

In this PNH patient with ESRD, renal anemia furtheraggravated the transfusion demand for this rare disorderthat is characterized by defective hematopoiesis.3 Ironoverload was therefore inevitable in our patient given themultiple and frequent blood transfusions, approximatingat least 300 units of PRBC (unit of blood = 250 mL) so

Correspondence to: Y.-M. Chen, MD, Department ofInternal Medicine, National Taiwan University HospitalYun-Lin Branch, Yun-Lin 640, Taiwan. E-mail:[email protected] conflicts of interest. All authors: no conflicts.Funding: No funding sources.

Figure 1 Secondary hemochromatosis. Axial magnetic reso-nance imaging with the T2-weighted fast-recovery fastspin-echo (FRFSE) sequence demonstrated significant accen-tuated decreases in liver and spleen signal intensities.

Hemodialysis International 2012; ••:••–••

© 2012 The AuthorsHemodialysis International © 2012 International Society for HemodialysisDOI:10.1111/j.1542-4758.2012.00704.x 1

Page 2: The administration of deferasirox in an iron-overloaded dialysis patient

far. Although the symptoms of secondary hemochroma-tosis are nonspecific, intolerable weakness, abdominalpain, and anorexia are symptoms that allowed the clini-cians to direct their attention to iron overload; this diag-nosis was supported by extremely high serum levels offerritin, transferrin saturation of >45%, and typical ironoverload on liver MRI. The challenge that followed wasdetermining how to successfully conduct chelatingtherapy in a dialysis patient with extreme iron accumu-lation. Borrowing from the experience of treating dialysispatients suffering from aluminum overload, DFO wastitrated gradually from a dosage of 10–40 mg/kg/weekand administered during a period of 1 year.4 However,no sign of clinical improvement was observed and serumferritin levels progressively increased to 12,123 ng/mL.Considering iron chelation therapy, deferasirox offeredan alternative option.5 Thus, we replaced the adminis-tration of intravenous DFO with that of oral deferasirox.We began with a dose of 15 mg/kg/d and slowly titratedthe dosage to a maximum of 30 mg/kg/d. The patientresponded well with a progressive decrease in serum fer-ritin levels during the follow-up period. Currently, undera daily dosage of 10 mg/kg/d, the patient remains freefrom iron overload symptoms, with serum ferritin levels

controlled at 3000–3500 ng/mL. Furthermore, ourpatient did not experience any significant complicationsfrom deferasirox administration, including skin rash,fever, or intolerable abdominal pain. It is also worthnoting that hypocalcemia, which is the only adverseeffect known to result from deferasirox use in a ESRDpatient, was also absent in our patient.6 This case dem-onstrates the effectiveness, safety, and tolerability ofdeferasirox administration in dialysis patients. Given thatdeferasirox may cause acute renal failure, creatinineclearance <40 mL/min and serum creatinine >2-fold theupper limit of normal are listed as contraindications byNovartis and the FDA.7 However, deferasirox has notbeen studied in patients with renal impairment. Itsmechanism of iron excretion is predominantly fecal, andboth deferasirox and its metabolites are primarilyexcreted in feces.7 Based on our experience, deferasiroxcan be hypothesized to be safe for patients with ESRDundergoing renal replacement therapy, for whom acuterenal failure is no longer a concern.

Manuscript received December 2011; revised March2012.

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Figure 2 Trends in serum ferritin levels and the dosages of deferoxamine and deferasirox administered from 2008 to 2010.*Axis scale of deferoxamine (DFO) is mg week and of deferasirox is mg per day.

Letter to the Editor

Hemodialysis International 2012; ••:••–••2

Page 3: The administration of deferasirox in an iron-overloaded dialysis patient

Ching-Wei TSAI,1,2 Feng-Jung YANG,1,2

Chun-Chieh HUANG,3 Chin-Chi KUO,1,2

Yung-Ming CHEN1,2

1Department of Internal Medicine, National Taiwan UniversityHospital Yun-Lin Branch, Yun-Lin, Taiwan;

2Department of Internal Medicine, National Taiwan UniversityHospital, Taipei, Taiwan;

3Department of Medical Imaging, Far Eastern MemorialHospital, Taipei, Taiwan

REFERENCES1 Kletzmayr J, Horl WH. Iron overload and cardiovascular

complications in dialysis patients. Nephrol Dial Transplant.2002; 17(Suppl 2):25–29.

2 Van Buren P, Velez RL, Vaziri ND, Zhou XJ. Iron overdose:A contributor to adverse outcomes in randomized trials of

anemia correction in CKD. Int Urol Nephrol. 2012;44:499–507.

3 Rimola J, Martin J, Puig J, Darnell A, Massuet A. Thekidney in paroxysmal nocturnal haemoglobinuria: MRIfindings. Br J Radiol. 2004; 77:953–956.

4 McCarthy JT, Milliner DS, Schmidt DF, Schniepp BJ, KurtzSB, Johnson WJ. Deferoxamine and coated charcoalhemoperfusion to remove aluminum in dialysis patients.Kidney Int. 1988; 34:804–808.

5 Nisbet-Brown E, Olivieri NF, Giardina PJ, et al. Effective-ness and safety of ICL670 in iron-loaded patients withthalassaemia: A randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet. 2003; 361:1597–1602.

6 Yusuf B, McPhedran P, Brewster UC. Hypocalcemia in adialysis patient treated with deferasirox for iron overload.Am J Kidney Dis. 2008; 52:587–590.

7 Hohneker JA. Exjade (deferasirox): Boxed warning. In:MedWatch: The FDA Safety Information and AdverseEvent Reporting Program; 2010.

Letter to the Editor

Hemodialysis International 2012; ••:••–•• 3